The Calcium-Sensing Receptor (CaR) and its Disorders

Abstract

The system that regulates extracellular calcium (Ca(2+o)) homeostasis maintains a nearly constant level of Ca(2+o) so as to ensure the availability of calcium for its numerous intra- and extracellular roles. The molecular cloning and characterization of a G protein-coupled, Ca(2+o)-sensing receptor has elucidated the mechanism through which parathyroid cells and other cell types involved in calcium homeostasis sense Ca(2+o) and initiate the homeostatic responses that maintain Ca(2+o) at its normal level. The identification of the CaR has also proven unequivocally that extracellular calcium ions serve in an informational capacity. Furthermore, the identification of inherited human disorders resulting from inactivating and activating mutations of the CaR that produce hyper- and hypocalcemia, respectively, has provided physiological proof of the essential role of the CaR in mineral ion metabolism. Finally, selective activators of the CaR, so-called calcimimetics, are in clinical trials for the treatment of primary and uremic hyperparathyroidism and will likely provide the first truly effective medical treatment of hyperparathyroidism. CaR antagonists (calcilytics) may also prove to be of clinical utility in settings where inhibition of the receptor would be desirable.